Nourianz (istradefylline) / Kyowa Kirin - LARVOL DELTA

Long-term outcomes associated with istradefylline versus catechol-O-methyltransferase inhibitors in patients with Parkinson's disease: a nationwide real-world cohort study. (PubMed, Parkinsonism Relat Disord) - "Istradefylline was associated with reduced mortality and treatment escalation but increased fracture risk compared with COMT inhibitors, supporting further evaluation of adenosine A2A antagonists."

Journal • Real-world evidence • Alzheimer's Disease • Cardiovascular • CNS Disorders • Dementia • Depression • Infectious Disease • Movement Disorders • Musculoskeletal Diseases • Orthopedics • Parkinson's Disease • Pneumonia • Psychiatry • Respiratory Diseases • ADORA2A • COMT

Involvement of Adenosine A2A Receptors in Anxiety-Like Behaviors in Tetrahydrocannabinol-Treated Mice. (PubMed, Brain Behav) - "These findings contribute to the understanding of THC's complex pharmacological actions, highlighting the importance of receptor cross talk in modulating anxiety and other behavioral outcomes."

Journal • Preclinical • Mood Disorders • Psychiatry • ADORA2A

Inhibition of Retinal AdoRA2a Activity Attenuates Myopia Progression. (PubMed, Invest Ophthalmol Vis Sci) - "Our results demonstrate that retinal AdoRA2a plays a pivotal role in myopia progression. Our findings identify the retina as the critical site for AdoRA2a's action and suggest an underlying AdoRA2a-Drd2 interaction mechanism, revealing the possible therapeutic potential of KW6002 in myopia progression."

Journal • Ophthalmology • ADORA2A • CD73 • DRD2 • ENTPD1 • NT5E

The persisting puzzle of OFF time in advanced Parkinson's disease. (PubMed, Brain) - "The complexity of managing motor fluctuations is further highlighted by the effectiveness of various non-dopaminergic adjunctive therapies for reducing OFF time in levodopa-treated patients, as shown by placebo-controlled clinical trials with adjunctive istradefylline, amantadine, zonisamide, and deep brain stimulation. For achieving better control of OFF time in advanced Parkinson's disease, there is a need for discovering therapeutic strategies acting beyond the limits of today's dopaminergic therapies. Modeling brain circuitry with tools like deterministic neural-computational analysis may provide valuable pharmacological and electrophysiological insights for better understanding of motor fluctuations and the choice of appropriate therapeutic targets."

Clinical • Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Selective antagonism of adenosine A2A receptor reduces hypobaric hypoxia-induced neuroinflammation by inhibiting cGAS-STING pathway. (PubMed, Sci Rep) - "Less cytosolic mtDNA accumulation after KW6002 treatment attenuated HY-induced activation of cGAS-STING inflammatory signaling pathway. ADORA2A activation mediates HY cognitive impairment, which is achieved by activating EPAC1 and VDAC1 to mediate mtDNA release and cGAS-STING signaling pathway to drive neuroinflammation cascade."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Inflammation • ADORA2A • ADORA2B • VDAC1

Caffeine Mitigates Adenosine-Mediated Angiogenic Properties of Choroidal Endothelial Cells Through Antagonism of A1 Adenosine Receptor and PI3K-AKT Axis. (PubMed, Cells) - "We recently showed that systemic caffeine administration suppressed CNV in vivo, an effect partly reproduced by the adenosine receptor A2A antagonist Istradefylline. Here, we investigated the cell-autonomous effects of caffeine on mouse choroidal endothelial cells, focusing on its role as an adenosine receptor antagonist and its potential to inhibit pathological neovascularization."

Journal • Age-related Macular Degeneration • CNS Disorders • Dry Age-related Macular Degeneration • Inflammation • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

Istradefylline induced psychosis: what is the role of adenosine? (PubMed, J Acad Consult Liaison Psychiatry) - No abstract available

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia

Drug Development. (PubMed, Alzheimers Dement) - "We recently developed a novel fluorinated derivative of the approved A2A receptor antagonist, Istradefylline (approved for Parkinson's disease), named MB204, for potential use in AD and depression...One hour after the final dose, general anesthesia (1.3% isoflurane) was administered to lower body temperature and induce Tau hyperphosphorylation, as described previously...A reduction was only seen with MB204 for the AT8 epitope (p<0.05) and only seen for lithium for the AT270 and pT205 epitope (p<0.01 and 0.001) Acute oral treatment of mice with MB204 reduced anesthesia induced Tau hyperphosphorylation at key clinically relevant Tau epitopes. These findings highlight MB204 potential as a therapeutic agent for AD and related tauopathies."

Journal • Alzheimer's Disease • Anesthesia • CNS Disorders • Depression • Movement Disorders • Parkinson's Disease • Psychiatry • ADORA2A

Treatment strategies for motor fluctuations in Parkinson's disease: a systematic review of efficacy, functionality, and drug accessibility with a focus on Latin America. (PubMed, Front Pharmacol) - "High-certainty evidence supports the efficacy of extended-release levodopa (IPX066), opicapone, pramipexole, rotigotine, and safinamide in reducing OFF-time, although improvements in functional disability and quality of life were modest or inconsistent. Moderate-certainty evidence supports device-aided therapies, including levodopa-carbidopa intestinal gel (LCIG), subcutaneous foslevodopa-foscarbidopa, and continuous apomorphine infusion, which achieved larger effects on OFF-time and functional outcomes...In contrast, several newer therapies-such as IPX066, opicapone, istradefylline, and foslevodopa-foscarbidopa-were unavailable in most Latin American markets, and price differentials for controlled-release or add-on therapies were often several-fold higher after PPP adjustment...The Latin American region exemplifies these disparities, with limited regulatory availability, heterogeneous pricing, and insufficient inclusion of novel agents in national formularies...."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease

Adenosine pathway as a therapeutic target in diffuse large B cell lymphoma (ASH 2025) - "Shortstimulation with A2AR agonist (CGS-21680) causes an increase in intracellular cAMP in some cell lines(HBL-1, Ly7, Ly1) but not in others (Ly19, Ly10). This increase in cAMP can be reverted with A2ARantagonists (ciforadenant and istradefylline)...Ciforadenant at both doses increased survival in B6but not in NOD-SCID mice, with time of death considered when tumors reached 2 cm and mice wereeuthanized (Log rank (Mantel-Cox) test p=0.019). Taken together our results demonstrate that DLBCLcells are resistant to the inhibitory effects of eADO seen in normal B cells, and that A2AR antagonists areeffective for the treatment DLBCL via an immune mediated mechanism in a preclinical model of DLBCL."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Solid Tumor • BCL2 • CD38 • CD73 • ENTPD1 • HLA-C • LY9 • NT5E • SDC1

Aberrant adenosine A2A receptor signaling in the choroid plexus drives CSF hypersecretion and ventriculomegaly in hydrocephalus. (PubMed, Nat Commun) - "Furthermore, we unveil ChP-A2AR signaling as a molecular mechanism linking brain insults with CSF hypersecretion through parallel PI3K/Akt-dependent activation of SPAK phosphorylation and NF-κB-dependent transcriptional regulation of ATP1A2. Lastly, the A2AR antagonist KW6002 protects against hydrocephalus induced by autologous blood and kaolin, offering a novel treatment for hydrocephalus by repurposing the FDA-approved A2AR antagonist istradefylline."

Journal • CNS Disorders • Ventriculomegaly • ADORA2A

Targeting the adenosine A2A receptor enhances the efficacy of low dose temozolomide in a murine glioma model (SNO 2025) - "Glioblastoma (GBM) remains one of the most aggressive brain tumors, with limited effective therapies including temozolomide (TMZ) and resistance to immunotherapy. The combination therapy significantly improved survival over sham (p = 0.0042), TMZ (p = 0.0029), and istradefylline (p = 0.0027). Our findings support the therapeutic relevance of A2AR in GBM and suggest that combining its inhibition with standard-of-care TMZ may enhance efficacy while reducing systemic toxicity."

IO biomarker • Preclinical • Brain Cancer • Glioblastoma • Glioma • Solid Tumor • ADORA2A • IFNG • PD-1 • THY1

Biphasic actions of the adenosine A2a receptor antagonist istradefylline in mice with obstructive uropathy. (PubMed, Sci Rep) - "The adenosine A2a receptor has both anti-inflammatory and profibrotic effects. The therapeutic window by which adenosine A2a receptor antagonism may slow CKD progression is thus relatively narrow, even when employing an agent with immediate clinical applicability."

Journal • Preclinical • Chronic Kidney Disease • CNS Disorders • Fibrosis • Immunology • Movement Disorders • Nephrology • Parkinson's Disease • Renal Disease • ADORA2A • COL1A1 • TGFB1

Targeting the adenosine A2A receptor enhances the efficacy of low dose temozolomide in a murine glioma model (WFNOS 2025) - "Glioblastoma (GBM) remains one of the most aggressive brain tumors, with limited effective therapies including temozolomide (TMZ) and resistance to immunotherapy. The combination therapy significantly improved survival over sham (p = 0.0042), TMZ (p = 0.0029), and istradefylline (p = 0.0027). Our findings support the therapeutic relevance of A2AR in GBM and suggest that combining its inhibition with standard-of-care TMZ may enhance efficacy while reducing systemic toxicity."

IO biomarker • Preclinical • Brain Cancer • Glioblastoma • Glioma • Solid Tumor • ADORA2A • IFNG • PD-1 • THY1

Terpenes from Cannabis sativa relieve neuropathic pain in mice via the Adenosine A2a Receptor expressed in Pax2+ spinal inhibitory interneurons (Neuroscience 2025) - "By utilizing CRISPR knockdown and the small molecule inhibitor istradefylline, we showed that terpenes act in CIPN through the activation of the Adenosine A2a Receptor (A2aR) in the spinal cord...Taken together, we show that terpenes have antinociceptive effects in neuropathic pain via the A2aR on Pax2+ inhibitory interneurons in mouse spinal cord. With this work, we aim to identify the detailed mechanism by which terpenes relieve neuropathic pain, and establish a scientific basis for their use as a novel non-opioid pain therapeutic."

Preclinical • CNS Disorders • Neuralgia • Pain • Peripheral Neuropathic Pain • ADORA2A • PAX2

Alzheimer s disease hypoperfusion is driven by an imbalance between A2A and A1 adenosine receptors (Neuroscience 2025) - " Aged (15-month-old) female 3xTg-AD and C57BL/6J mice were treated with istradefylline (A2AR antagonist - 2 mg/kg/day, IP) or tecadenoson (A1R agonist - 15 μg/kg, IP) for 7 days... Although agonism of A1R were not sufficient to restore A2AR/A1R balance, blockage of A2AR were. We are considering a different pharmacological approach to improve A1R, to mimic the improvements observed with A2AR blockage."

Alzheimer's Disease • CNS Disorders • TJP1

Cisplatin-induced disruption in reward-motivated behavior is associated with microglial reactivity and impaired medium spiny neuron morphology in the striatum (Neuroscience 2025) - "Our preliminary data also indicate that the A2A receptor antagonists KW6002 and caffeine attenuate cisplatin-induced nesting impairments...Our findings suggest that cisplatin impairs nesting-related reward-motivated behavior, striatal MSN morphology, and that microglial activation may be associated with emotive dysfunction in CICI. In summary, our studies identify novel therapeutic targets that can be targeted to improve the quality of life for cancer survivors."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • ADORA2A • CD68

Acute Adenosine Receptor Antagonism in Combination With Acute Intermittent Hypoxia to Promote Breathing Plasticity in Amyotrophic Lateral Sclerosis: Protocol for a Randomized, Double-Blinded, Placebo-Controlled Trial. (PubMed, JMIR Res Protoc) - P1/2 | "These aims will provide crucial data regarding the preliminary safety and feasibility of this paired intervention and help optimize therapeutic AIH as a rehabilitation strategy, thereby guiding further research concerning this novel treatment for ALS."

Clinical • Clinical protocol • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Levodopa-induced dyskinesia in Parkinson's disease: an updated review of pharmacological treatments. (PubMed, Front Aging Neurosci) - "Despite decades of investigation, only amantadine has been established as the standard FDA-approved treatment, while istradefylline provides a complementary non-dopaminergic option. Most other candidate agents-including memantine, clozapine, and serotonergic or noradrenergic modulators-have shown inconsistent efficacy or safety limitations, underscoring persistent translational challenges between preclinical promise and clinical outcomes...Potential complementary pathways, including Traditional Chinese Medicine (TCM), are also briefly noted as alternative directions. By linking mechanistic insights with therapeutic evidence, this review provides an updated framework for optimizing LID management and guiding future research directions."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease

Adenosine A2A receptor modulation affects the development of depressive-like behaviour and dopamine D2 receptor availability in rats exposed to repeated social defeat. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Our study showed that the treatment with either an A2AR agonist or an A2AR antagonist prevented the development of depressive-like behaviour, and reduced the availability of D2 receptor in the striatum after exposure to RSD most likely by modulating the receptor affinity."

Journal • Preclinical • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • ADORA2A • DRD2

Combining Low Oxygen Therapy and an Adenosine A2a Receptor Antagonist to Improve Functional Mobility After Spinal Cord Injury (clinicaltrials.gov) - P1/2 | N=40 | Not yet recruiting | Sponsor: Randy Trumbower, PT, PhD | Trial completion date: Jun 2027 ➔ Jun 2028 | Trial primary completion date: Dec 2026 ➔ Dec 2027

Trial completion date • Trial primary completion date • CNS Disorders • Musculoskeletal Diseases • Orthopedics

Istradefylline for Freezing of Gait in Parkinson's Disease: A Systematic Review and Meta-Analysis (MDS Congress 2025) - "Istradefylline demonstrated a modest improvement in UPDRS scores and a more pronounced effect on FOG-Q scores, suggesting potential benefits for FOG in PD. These findings highlight the need for more extensive randomized controlled trials to confirm istradefylline's efficacy in managing gait disturbances in PD patients. Figure 1"

Retrospective data • Review • CNS Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • ADORA2A

Parkinsonism after Post-Anoxic Brain Injury (MDS Congress 2025) - "Carbidopa-levodopa and istradefylline offered little benefit for FOG. Patient experienced partial improvement in gait with amantadine... Parkinsonism is a rare manifestation that may be encountered in post-anoxic patients with basal ganglia injury. Differences in symptoms and response to medications may be due to extent of basal ganglia damage. DaT scan may be considered for further verification of parkinsonism in anoxia."

CNS Disorders • Movement Disorders • Parkinson's Disease • Vascular Neurology

Cognitive Effects of Istradefylline in Parkinson's Disease: A 26-Week Open-Label Pilot Study (MDS Congress 2025) - "These findings provide preliminary evidence that istradefylline may improve broad aspects of cognition in PD, particularly in executive function, attention, and memory. While suggestive, these results require confirmation in a randomized and controlled trial."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Movement Disorders • Parkinson's Disease • ADORA2A

Adenosine A2A receptor activation in the nucleus accumbens decreases motivation for wheel running in male mice. (PubMed, Psychopharmacology (Berl)) - "These findings demonstrate that, in male mice, A2A receptor activation selectively suppressed the appetitive component of wheel-running motivation, whereas A2A receptor blockade did not. Together, our results highlight the crucial role of NAc A2A receptors in regulating motivation for wheel running and suggest the potential therapeutic application of A2A receptor agonists for treating maladaptive behavioral over-engagement."

Journal • Preclinical • CNS Disorders • Psychiatry • ADORA2A